| Abstract
| - The N-methyl groups of N,N‘-dimethylpiperazine (Me2ppz) lie uniquely in the coordination plane of Me2ppzPt(5‘-GMP)2, which has a high percentage of the head-to-head (HH) form. Examples of reported Pt compounds with ligands lacking NH groups do not form HH adducts and lack anticancer activity. These ligands have bulk projecting from this plane. We hypothesize that the small size and not the H-bonding ability of NH3 is the key feature favoring the HH form and leading to the excellent activity of cisplatin.
- Most simple cis-PtA2G2 complexes that model the G−G cross-link DNA lesions caused by the clinically usedanticancer drug cis-PtCl2(NH3)2 undergo large fluxional motions at a rapid rate (A2 = two amines or a diamine;G = guanine derivative). The carrier amine ligands in active compounds have NH groups, but the fundamentalrole of the NH groups has been obscured by the dynamic motion. To assess carrier ligand effects, we examineretro models, cis-PtA2G2 complexes, in which dynamic motion has been reduced by the incorporation of stericbulk into the carrier ligands. In this study we introduce a new approach employing the chirality-neutral chelate(CNC) ligand, Me2ppz (N,N‘-dimethylpiperazine). Because they lie in the Pt coordination plane, the methyl groupsof Me2ppz do not clash with the O6 of the base of G ligands in the ground state, but such clashes stericallyhinder dynamic motion. NMR spectroscopy provided conclusive evidence that Me2ppzPt(GMP)2 complexes(GMP = 5‘- and 3‘-GMP) exist as a slowly interconverting mixture of two dominant head-to-tail (HT) conformersand a head-to-head (HH) conformer. Since the absence of carrier ligand chirality precluded using NMR methodsto determine the absolute conformation of the two HT conformers, we used our recently developed CD pH jumpmethod to establish chirality. The most abundant HT Me2ppzPt(5‘-GMP)2 form had Λ chirality. Previously thischirality was shown to be favored by phosphate-cis G N1H hydrogen-bonding interligand interactions; suchinteractions also favor the HT conformers over the HH conformer. For typical carrier ligands, G O6 and phosphateinteractions with the carrier ligand NH groups also favor the HT forms. These latter interactions are absent inMe2ppzPt(GMP)2 complexes, but the HT forms are still dominant. Nevertheless, we do find the first evidence foran HH form of a simple cis-PtA2G2 model with A2 lacking any NH groups. In previous studies, the absence ofthe HH conformer in cis-PtA2G2 complexes lacking carrier NH groups may be due to the presence of out-of-plane carrier ligand bulk. Such bulk forces both G O6−G O6 and G O6−carrier ligand clashes, thereby disfavoringthe HH form. The major DNA cross-link adduct has the HH conformation. Thus, for anticancer activity, thesmall bulk of the NH group may be more important than the H-bonding interaction.
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